View metadata, citation and similar papers at core.ac.uk brought to you by CORE

provided by Frontiers - Publisher Connector EDITORIAL published: 31 December 2013 doi: 10.3389/fphar.2013.00160 Novel insights which may translate into treatments for irritable bowel syndrome

Angelo A. Izzo*

Department of Pharmacy, University of Naples Federico II, Naples, Italy *Correspondence: [email protected]

Edited by: Gareth J. Sanger, Queen Mary University of London, UK

Keywords: 5-hydroxytryptamine, brain-gut axis, cannabinoid receptors, enkephalinase inhibitors, irritable bowel syndrome, kynurenine pathway, pharmacotherapy, toll-like receptors

Irritable bowel syndrome (IBS) is a very common functional A pan-Irish study investigated the consequences of toll-like disorder of the digestive tract. Despite the prevalence and the receptors (TRLs) activation on the production of kynurenine social impact of IBS, the exact etiopathogenesis is incomplete and (i.e., one of the metabolites of the kynurenine pathways derived the pharmacological treatment is unsatisfactory. In this research from tryptophan) in IBS (Clarke et al., 2012). Whole blood from topic, Frontiers in Pharmacology brings together a group of review IBS patients and healthy controls was cultured with a num- and original articles focusing on IBS. ber of TLR agonists. Tryptophan and kynurenine were assayed, Fabrizio De Ponti brilliantly outlined the drugs currently used by HPLC, both in the plasma and in cell culture supernatants. in—or in development for—IBS, within a scenario in which IBS subjects had an elevated plasma kynurenine:tryptophan ratio the specific armamentarium of medications is unsatisfactory (De compared to healthy controls, which is suggestive of tryptophan Ponti, 2013). Jakub Fichna and Martin Storr focused their review metabolism via the kynurenine pathway. Furthermore, a differen- article on the disturbances in the brain-gut axis as possible cause tial downstream profile of kynurenine production subsequent to of IBS (Fichna and Storr, 2012). The Authors illustrated the TLR activation in IBS patients - compared to healthy controls – pathophysiological mechanisms which contribute to the genera- was demonstrated. Collectively, such results suggest (1) that a tion of IBS symptoms, with a special emphasis to stress, emotion pharmacological modulation of TLRs, by controlling the abnor- and psychological factors. The future of anti-IBS drugs target- mal kynurenine pathway, be a novel potential strategy for IBS and ing the brain-gut axis were also highlighted. The bidirectional (2) the use of plasma tryptophan metabolites assay as a biomarker communication between the brain and the gut opens up new for IBS diagnosis. treatment possibility for IBS patients with mood disturbances Beattie et al. investigated the in vitro and in vivo pharmaco- that are refractory to first-and second-lines therapies. dynamic properties of a novel 5-HT4 receptor agonist, namely Jeremy Gale and Lesley Houghton reviewed the preclinical and TD-8954 (Beattie et al., 2011). TD-8954 was found to be a potent clinical data which support the potential use of gabapentin and (pKi = 9.4) and selective (>2000-fold over the all other 5-HT pregabalin in disorders characterized by visceral hypersensitivity, receptors and over a plethora of receptors, enzymes, and ion such as IBS (Gale and Houghton, 2011). Both gabapentin and channels) 5-HT4 receptor agonist in vitro with strong in vivo gas- pregabalin bind with high affinity to alpha 2 delta subunits of trointestinal activity in guinea pigs, rats, dogs, and in healthy voltage-gated calcium channels and inhibit both visceral nocicep- humans. TD-8954 may have value in the treatment in C-IBS tion and motility. Although limited, clinical studies on visceral sufferers. pain are in agreement with animal results and support a con- Interleukin-6 (IL-6) is elevated in the plasma of D-IBS tinued research and development of the alpha 2 delta ligands patients (Rana et al., 2012) and IL-6 gene polymorphisms may in IBS. change individual susceptibility to IBS (Barkhordari et al., 2010). Eberlin et al. reviewed the pharmacokinetics, pharmacody- O’Malley et al. evaluated the effect of IL-6 on colonic ion trans- namics and clinical data of racecadotril, a powerful and selective port (a measure of intestinal absorption and secretion) in the enkephalinase inhibitor, which has emerged as a promising drug distal colon of the Wistar Kyoto rat (WKY) (O’Malley et al., 2012), in the antisecretory therapy (Eberlin et al., 2012). In multiple a pre-clinical model for IBS. In colonic sheets mounted in Using direct comparative studies, racecadotril was at least as effective chambers, IL-6 evoked secretion preferentially in WKY colons as loperamide in the treatment of acute diarrhoea, and exhibited (as compared to control rats) and this effect was believed to be significantly better tolerability. Although the results are robust due to increased sensitivity of submucosal neurons to the pro- and encouraging, the potential of racecadotril in D-IBS patients inflammatory cytokine. Such results bolsters our knowledge of remains to be established. IL-6 as a contributory factor in the pathophysiology of IBS. Cannabinoids—via CB1 and/or CB2 receptor activation— exert pharmacological actions which are potentially beneficial Abbreviations: 5-HT, 5-hydroxytryptamine; C-IBS, constipation predominant in IBS (Izzo and Coutts, 2005; Storr et al., 2008). Kimball irritable bowel syndrome; D-IBS, diarrhoea predominant irritable bowel syn- et al. evaluated the effect of selective cannabinoid receptor ago- drome; hInEpCs, human intestinal epithelial cells; IBS, irritable bowel syndrome; IL-6, interleukin-6; iPSC induced pluripotent stem cell; PI-IBS, post-inflammatory nists in a mouse model of accelerated upper gastrointestinal irritable bowel syndrome; TLRs, toll-like receptors; WKY, Wistar Kyoto rat. transit resembling post-inflammatory IBS (PI-IBS) (Kimball

www.frontiersin.org December 2013 | Volume 4 | Article 160 | 1 Izzo IBS pharmacology

et al., 2010). The experimental model is generated by intracolonic pathway downstream of toll-Like receptor activation in irritable bowel syn- administration of mustard oil, which induce transient colitis and, drome. Front. Pharmacol. 3:90. doi: 10.3389/fphar.2012.00090 in the longer term (i.e., 28 days after mustard oil) a functional De Ponti, F. (2013). Drug development for the irritable bowel syndrome: current challenges and future perspectives. Front. Pharmacol. 4:7. doi: increase in gastrointestinal transit that is observed when there is 10.3389/fphar.2013.00007 no inflammation (Kimball et al., 2005). It was found that both Eberlin, M., Mück, T., and Michel, M.C. (2012). A comprehensive review cannabinoid receptor subtypes were up-regulated in the small of the pharmacodynamics, pharmacokinetics, and clinical effects of the intestine, an effect closely associated to increased efficacy of both neutral endopeptidase inhibitor racecadotril. Front. Pharmacol. 3:93. doi: CB and CB receptor agonists in normalizing the accelerated 10.3389/fphar.2012.00093 1 2 Fichna, J., and Storr, M. A. (2012). Brain-Gut Interactions in IBS. Front. Pharmacol. transit (Kimball et al., 2010). These results suggest that the altered 3:127. doi: 10.3389/fphar.2012.00127 cannabinoid CB1 and CB2responsiveness is maintained long after Gale, J. D., and Houghton, L. A. (2011). Alpha 2 delta (α(2)δ) ligands, gabapentin an initial inflammatory period and suggest a role of cannabinoid and pregabalin: what is the evidence for potential use of these ligands in receptors in the underlying pathophysiology of PI-IBS. irritable bowel syndrome. Front. Pharmacol. 2:28. doi: 10.3389/fphar.2011. The differentiated Caco-2 cells intestinal cell line, derived from 00028 Izzo, A. A., and Coutts, A. A. (2005). Cannabinoids and the digestive tract. Handb. a human colon carcinoma has been used for drug absorption Exp. Pharmacol. 168, 573–598. doi: 10.1007/3-540-26573-2_19 studies as well as to evaluate the epithelial barrier integrity in Kauffman, A. L., Gyurdieva, A. V., Mabus, J. R., Ferguson, C., Yan, Z., and Hornby, relation to IBS as well as to investigate the intestinal permeabil- P. J. (2013). Alternative functional in vitro models of human intestinal epithelia. ity of IBS drugs (Catalioto et al., 2008; Piche et al., 2009). Within Front. Pharmacol. 4:79. doi: 10.3389/fphar.2013.00079 Kimball, E. S., Palmer, J. M., D’Andrea, M. R., Hornby, P. J., and Wade, our research topic on IBS, Kauffman et al. compared two alterna- P. R. (2005). Acute colitis induction by oil of mustard results in later tive sources of human intestinal cells, i.e., commercially available development of an IBS-like accelerated upper GI transit in mice. Am. J. primary human intestinal epithelial cells (hInEpCs) and induced Physiol. Gastrointest. Liver Physiol. 288, G1266–G1273. doi: 10.1152/ajpgi.004 pluripotent stem cell (iPSC)-derived intestinal cells, to Caco-2, 44.2004 for possible use in intestinal transport assays (Kauffman et al., Kimball, E. S., Wallace, N. H., Schneider, C. R., D’Andrea, M. R., and Hornby, P. J. (2010). Small intestinal cannabinoid receptor changes following a sin- 2013). Measurements of intestinal marker expression, forma- gle colonic insult with oil of mustard in mice. Front. Pharmacol. 1:132. doi: tion of monolayers with tight junction formation and functional 10.3389/fphar.2010.00132 molecule transport and binding revealed that primary hInEpCs O’Malley, D., Dinan, T. G., and Cryan J. F. (2012). Interleukin-6 modulates colonic and iPSC-derived intestinal cells could offer an alternative source transepithelial ion transport in the stress-sensitive wistar kyoto rat. Front. of human intestinal cells for understanding intestinal epithelial Pharmacol. 3:190. doi: 10.3389/fphar.2012.00190 Piche, T., Barbara, G., Aubert, P., Bruley des Varannes, S., Dainese, R., Nano, J. L., patho(physiology) and drug transport. et al. (2009). Impaired intestinal barrier integrity in the colon of patients with In summary, this research topic should provide a useful irritable bowel syndrome: involvement of soluble mediators. Gut 58, 196–201. resource for IBS researchers, both basic and clinical. The pharma- doi: 10.1136/gut.2007.140806 cological studies, together with new strategies for drug discovery, Rana, S. V., Sharma, S., Sinha, S. K., Parsad, K. K., Malik, A., and Singh, highlight that more research is urgently required to translate novel K. (2012). Pro-inflammatory and anti-inflammatory cytokine response in diarrhoea-predominant irritable bowel syndrome patients. Trop. Gastroenterol. and innovative basic concepts into prescribing options for health- 33, 251–256. doi: 10.7869/tg.2012.66 care professionals. It is hoped that this collection of articles will Storr, M. A., Yüce, B., Andrews, C. N., and Sharkey, K.A. (2008). The role of the inspire further research into IBS. endocannabinoid system in the pathophysiology and treatment of irritable bowel syndrome. Neurogastroenterol. Motil. 20, 857–868. doi: 10.1111/j.1365- REFERENCES 2982.2008.01175.x Barkhordari, E., Rezaei, N., Ansaripour, B., Larki, P., Alighardashi, M., Ahmadi- Ashtiani, H. R., et al. (2010). Proinflammatory cytokine gene polymorphisms Received: 27 November 2013; accepted: 06 December 2013; published online: 31 in irritable bowel syndrome. J. Clin. Immunol. 30, 74–79. doi: 10.1007/s10875- December 2013. 009-9342-4 Citation: Izzo AA (2013) Novel insights which may translate into treatments for Beattie, D. T., Armstrong, S. R., Vickery, R. G., Tsuruda, P. R., Campbell, C. B., irritable bowel syndrome. Front. Pharmacol. 4:160. doi: 10.3389/fphar.2013.00160 Richardson, C., et al. (2011). The pharmacology of TD-8954, a potent and selec- This article was submitted to Gastrointestinal Pharmacology, a section of the journal tive 5-HT(4) receptor agonist with gastrointestinal prokinetic properties. Front. Frontiers in Pharmacology. Pharmacol. 2:25. doi: 10.3389/fphar.2011.00025 Copyright © 2013 Izzo. This is an open-access article distributed under the Catalioto, R. M., Triolo, A., Giuliani, S., Altamura, M., Evangelista, S., and Maggi, terms of the Creative Commons Attribution License (CC BY). The use, dis- C. A. (2008). Increased paracellular absorption by bile salts and P-glycoprotein tribution or reproduction in other forums is permitted, provided the origi- stimulated efflux of otilonium bromide in Caco-2 cells monolayers as a model nal author(s) or licensor are credited and that the original publication in of intestinal barrier. J. Pharm. Sci. 97, 4087–4100. doi: 10.1002/jps.21240 this journal is cited, in accordance with accepted academic practice. No use, Clarke, G., McKernan, D. P., Gaszner, G., Quigley, E. M., Cryan, J. F., and Dinan, distribution or reproduction is permitted which does not comply with these T.G. (2012). A distinct profile of tryptophan metabolism along the kynurenine terms.

Frontiers in Pharmacology | Gastrointestinal Pharmacology December 2013 | Volume 4 | Article 160 | 2